In order to gain new insight into the biochemical basis of cystic fibrosis we propose to study the mucin(s) responsible for the increased viscosity of the sputum in these patients. This mucin will be isolated from normal individuals and patients with cystic fibrosis and analyzed by various chemical and biophysical techniques for any qualitative or quantitative differences. The biochemical basis for the increased studies will give additional clues to identify other chemical means of decreasing the viscosity of sputum. The third area to be studied is that of designing new mucolytic agents. Special emphasis will be placed on identifying orally active drugs that can be administered as prodrugs and activated in vivo to the active component. We have recently identified such an agent WR 2721, NH2 CH2 CH2 CH2 NHCH2 CH2 SPO3 H2. The thiophosphonate of this compound is split enzymatically in the body to form the active drug. After oral or parenteral administration the drug can be found in the lungs and trachea of experimental animals. Since a significant amount of pharmacology and toxicology has previously been done on this compound, it was possible to obtain an Investigational New Drug Application from the Food and Drug Administration; a clinical evaluation of this compound is currently under way. We hope that this drug will serve as a prototype for a number of other mucolytic agents.